HOME

TheInfoList



OR:

The thiazolidinediones , abbreviated as TZD, also known as glitazones after the prototypical drug ciglitazone, are a class of
heterocyclic compounds A heterocyclic compound or ring structure is a cyclic compound that has atoms of at least two different elements as members of its ring(s). Heterocyclic chemistry is the branch of organic chemistry dealing with the synthesis, properties, an ...
consisting of a five-membered C3NS ring. The term usually refers to a family of drugs used in the treatment of
diabetes mellitus type 2 Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urinati ...
that were introduced in the late 1990s.


Mechanism of action

Thiazolidinediones or TZDs act by activating
PPAR In the field of molecular biology, the peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes. PPARs play essential roles in the reg ...
s (peroxisome proliferator-activated receptors), a group of
nuclear receptors In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These receptors work with other proteins to regulate the expression of specif ...
, specific for '' PPARγ'' (PPAR-gamma, PPARG). They are thus the PPARG agonists subset of PPAR agonists. The endogenous
ligand In coordination chemistry, a ligand is an ion or molecule (functional group) that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's elect ...
s for these receptors are free
fatty acid In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, f ...
s (FFAs) and eicosanoids. When activated, the receptor binds to DNA in complex with the retinoid X receptor (RXR), another nuclear receptor, increasing transcription of a number of specific
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a b ...
s and decreasing transcription of others. The main effect of expression and repression of specific genes is an increase in the storage of fatty acids in adipocytes, thereby decreasing the amount of fatty acids present in circulation. As a result, cells become more dependent on the oxidation of
carbohydrates In organic chemistry, a carbohydrate () is a biomolecule consisting of carbon (C), hydrogen (H) and oxygen (O) atoms, usually with a hydrogen–oxygen atom ratio of 2:1 (as in water) and thus with the empirical formula (where ''m'' may or m ...
, more specifically
glucose Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, u ...
, in order to yield energy for other cellular processes.


PPARγ transactivation

The activated PPAR/RXR
heterodimer In biochemistry, a protein dimer is a macromolecular complex formed by two protein monomers, or single proteins, which are usually non-covalently bound. Many macromolecules, such as proteins or nucleic acids, form dimers. The word ''dimer'' ha ...
binds to peroxisome proliferator
hormone response element Response elements are short sequences of DNA within a gene promoter or enhancer region that are able to bind specific transcription factors and regulate transcription of genes. Under conditions of stress, a transcription activator protein bin ...
s upstream of target genes in complex with a number of coactivators such as
nuclear receptor coactivator 1 The nuclear receptor coactivator 1 (''NCOA1'') is a transcriptional coregulatory protein that contains several nuclear receptor interacting domains and an intrinsic histone acetyltransferase activity. NCOA1 is recruited to DNA promotion sites by ...
and
CREB binding protein Cyclic adenosine monophosphate Response Element Binding protein Binding Protein (CREB-binding protein), also known as CREBBP or CBP or KAT3A, is a coactivator encoded by the ''CREBBP'' gene in humans, located on chromosome 16p13.3. CBP has intrin ...
, this causes upregulation of genes (for a full list see PPARγ): * Insulin resistance is decreased *
Adipocyte Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through adipogenesis. I ...
differentiation is modified *
VEGF Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors ...
-induced angiogenesis is inhibited *
Leptin Leptin (from Greek λεπτός ''leptos'', "thin" or "light" or "small") is a hormone predominantly made by adipose cells and enterocytes in the small intestine that helps to regulate energy balance by inhibiting hunger, which in turn dimi ...
levels decrease (leading to an increased appetite) * Levels of certain interleukins (e.g. IL-6) fall *
Antiproliferative Cytostasis (cyto – cell; stasis – stoppage) is the inhibition of cell growth and multiplication. Cytostatic refers to a cellular component or medicine that inhibits cell division. Cytostasis is an important prerequisite for structured multic ...
action * Adiponectin levels rise TZDs also increase the synthesis of certain proteins involved in fat and glucose metabolism, which reduces levels of certain types of lipids, and circulating free fatty acids. TZDs generally decrease triglycerides and increase high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C). Although the increase in LDL-C may be more focused on the larger LDL particles, which may be less atherogenic, the clinical significance of this is currently unknown. Nonetheless, rosiglitazone, a certain glitazone, was suspended from allowed use by medical authorities in Europe, as it has been linked to an increased risk of heart attack and stroke.


PPARγ transrepression

Binding of PPARγ to coactivators appears to reduce the levels of coactivators available for binding to pro-inflammatory transcription factors such as NF-κB; this causes a decrease in transcription of a number of pro inflammatory genes, including various interleukins and tumour necrosis factors.


Members of the class

Chemically, the members of this class are derivatives of the parent compound thiazolidinedione, and include: * Pioglitazone (Actos), France and Germany have suspended its sale after a study suggested the drug could raise the risk of bladder cancer. * Rosiglitazone (Avandia), which was put under selling restrictions in the US and withdrawn from the market in Europe due to some studies suggesting an increased risk of cardiovascular events. Upon re-evaluation of new data in 2013, the FDA lifted the restrictions. * Lobeglitazone (Duvie), approved for use in Korea Experimental, failed and non-marketed agents include: * Ciglitazone * Darglitazone * Englitazone * Netoglitazone * Rivoglitazone * Troglitazone (Rezulin), withdrawn due to increased incidence of drug-induced
hepatitis Hepatitis is inflammation of the liver tissue. Some people or animals with hepatitis have no symptoms, whereas others develop yellow discoloration of the skin and whites of the eyes ( jaundice), poor appetite, vomiting, tiredness, abdominal ...
. * Balaglitazone (DRF-2593) - developed by Dr Reddy's Laboratories, discontinued during 2010-11 phase III trials as no better than available molecules.
AS-605240
48450-29-7Replacing one oxygen atom in a thiazolidinedione with an atom of sulfur gives a
rhodanine Rhodanine is a 5-membered heterocyclic organic compound possessing a thiazolidine core. It was discovered in 1877 by Marceli Nencki who named it ''"Rhodaninsaure"'' in reference to its synthesis from ammonium rhodanide (known as ammonium thiocy ...
.


Uses

The only approved use of the thiazolidinediones is in
diabetes mellitus Diabetes, also known as diabetes mellitus, is a group of metabolic disorders characterized by a high blood sugar level ( hyperglycemia) over a prolonged period of time. Symptoms often include frequent urination, increased thirst and increased ...
type 2. According to a 2014 Cochrane systematic review of four
randomized controlled trial A randomized controlled trial (or randomized control trial; RCT) is a form of scientific experiment used to control factors not under direct experimental control. Examples of RCTs are clinical trials that compare the effects of drugs, surgical t ...
s, PPARγ-agonists may be effective in preventing further
stroke A stroke is a disease, medical condition in which poor cerebral circulation, blood flow to the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemorr ...
s in those who have already had a stroke or a transient ischemic attack (TIA) and may stabilize
atherosclerotic plaques Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheroma, atheromatous plaque. At onset there are usu ...
in the carotid arteries.


Research

Experimental investigations on TZDs have been carried out since 2005 in
polycystic ovary syndrome Polycystic ovary syndrome, or PCOS, is the most common endocrine disorder in women of reproductive age. The syndrome is named after the characteristic cysts which may form on the ovaries, though it is important to note that this is a sign and no ...
(PCOS), non-alcoholic steatohepatitis (NASH),
psoriasis Psoriasis is a long-lasting, noncontagious autoimmune disease characterized by raised areas of abnormal skin. These areas are red, pink, or purple, dry, itchy, and scaly. Psoriasis varies in severity from small, localized patches to comple ...
,
autism The autism spectrum, often referred to as just autism or in the context of a professional diagnosis autism spectrum disorder (ASD) or autism spectrum condition (ASC), is a neurodevelopmental condition (or conditions) characterized by difficulti ...
, ovarian hyperstimulation syndrome (by VEGF inhibition in granulosa cells), lichen planopilaris, and other conditions.Clinical Trials for Rosiglitazone
- from ClinicalTrials.gov, a service of the U.S.
National Institutes of Health The National Institutes of Health, commonly referred to as NIH (with each letter pronounced individually), is the primary agency of the United States government responsible for biomedical and public health research. It was founded in the lat ...
Several forms of lipodystrophy cause insulin resistance, which has responded favorably to thiazolidinediones. There are some indications that thiazolidinediones provide some degree of protection against the initial stages of breast carcinoma development. Evidence was emerging in 2008 that
vitamin E Vitamin E is a group of eight fat soluble compounds that include four tocopherols and four tocotrienols. Vitamin E deficiency, which is rare and usually due to an underlying problem with digesting dietary fat rather than from a diet low in vi ...
with thiazolidinediones is effective in the treatment of non-alcoholic steatohepatitis due to their combined antioxidant and insulin sensitizing effects, producing histological improvements in steatosis severity.


Side effects and contraindications

The withdrawal of troglitazone has led to concerns of the other thiazolidinediones also increasing the incidence of
hepatitis Hepatitis is inflammation of the liver tissue. Some people or animals with hepatitis have no symptoms, whereas others develop yellow discoloration of the skin and whites of the eyes ( jaundice), poor appetite, vomiting, tiredness, abdominal ...
and potential liver failure, an approximately 1 in 20,000 individual occurrence with troglitazone. Because of this, the FDA recommends two to three month checks of liver enzymes for the first year of thiazolidinedione therapy to check for this rare but potentially catastrophic complication. To date, 2008, the newer thiazolidinediones, rosiglitazone and pioglitazone have been free of this problem. The main side effect of all thiazolidinediones is water retention, leading to
edema Edema, also spelled oedema, and also known as fluid retention, dropsy, hydropsy and swelling, is the build-up of fluid in the body's tissue. Most commonly, the legs or arms are affected. Symptoms may include skin which feels tight, the area ma ...
, generally a problem in less than 5% of individuals, but a big problem for some and potentially, with significant water retention, leading to a decompensation of potentially previously unrecognized
heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, ...
. Therefore, thiazolidinediones should be prescribed with both caution and patient warnings about the potential for water retention/weight gain, especially in patients with decreased ventricular function (
NYHA The New York Heart Association (NYHA) Functional Classification provides a simple way of classifying the extent of heart failure. It places patients in one of four categories based on how much they are limited during physical activity; the limitatio ...
grade III or IV heart failure). Though older studies suggested there may be an increased risk of coronary heart disease and heart attacks with rosiglitazone, pioglitazone treatment, in contrast, has shown significant protection from both micro- and macro-vascular cardiovascular events and plaque progression. These studies led to a period of Food and Drug Administration advisories (2007 - 2013) that, aided by extensive media coverage, led to a substantial decrease in rosiglitazone use. In November 2013, the FDA announced it would remove the usage restrictions for rosiglitazone in patients with coronary artery disease. The new recommendations were largely based on the reasoning that prior meta-analyses leading to the original restrictions were not designed to assess cardiac outcomes and, thus, not uniformly collected or adjudicated. In contrast, one of the largest trials (RECORD trial) that was specifically designed to assess cardiac outcomes found no increased risk of
myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which ma ...
with rosiglitazone use, even after independent re-evaluation for FDA review. A 2013
meta-analysis A meta-analysis is a statistical analysis that combines the results of multiple scientific studies. Meta-analyses can be performed when there are multiple scientific studies addressing the same question, with each individual study reporting m ...
concluded that use of pioglitazone is associated with a slightly higher risk of
bladder cancer Bladder cancer is any of several types of cancer arising from the tissues of the urinary bladder. Symptoms include blood in the urine, pain with urination, and low back pain. It is caused when epithelial cells that line the bladder become ma ...
compared to the general population. The authors of the same analysis recommended that other blood sugar lowering agents be considered in people with other risk factors for bladder cancer such as cigarette smoking, family history, or exposure to certain forms of
chemotherapy Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemother ...
. A 2020 Cochrane systematic review did not find enough evidence of reduction of all-cause mortality, serious adverse events, cardiovascular mortality, non-fatal
myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which ma ...
, non-fatal
stroke A stroke is a disease, medical condition in which poor cerebral circulation, blood flow to the brain causes cell death. There are two main types of stroke: brain ischemia, ischemic, due to lack of blood flow, and intracranial hemorrhage, hemorr ...
or
end-stage renal disease Chronic kidney disease (CKD) is a type of kidney disease in which a gradual loss of kidney function occurs over a period of months to years. Initially generally no symptoms are seen, but later symptoms may include leg swelling, feeling tired, v ...
when comparing metformin monotherapy to Thiazolidinedione for treatment of
type 2 diabetes Type 2 diabetes, formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent urinatio ...
. Thiazolidinediones reduce
bone mineral density Bone density, or bone mineral density, is the amount of bone mineral in bone tissue. The concept is of mass of mineral per volume of bone (relating to density in the physics sense), although clinically it is measured by proxy according to optical ...
and increase the risk of fractures in women, possibly as a result of biasing the differentiation of bone marrow stromal cells away from
osteoblast Osteoblasts (from the Greek language, Greek combining forms for "bone", ὀστέο-, ''osteo-'' and βλαστάνω, ''blastanō'' "germinate") are cell (biology), cells with a single Cell nucleus, nucleus that synthesize bone. However, in the p ...
differentiation and toward
adipocyte Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through adipogenesis. I ...
formation. Thiazolidinediones increase expression of angiotensin-converting enzyme 2 (ACE2). It is hypothesized that this increases the chance of serious infection with the
SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) is a strain of coronavirus that causes COVID-19 (coronavirus disease 2019), the respiratory illness responsible for the ongoing COVID-19 pandemic. The virus previously had a ...
virus, which causes
COVID-19 Coronavirus disease 2019 (COVID-19) is a contagious disease caused by a virus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first known case was identified in Wuhan, China, in December 2019. The disease quick ...
.


References

{{PPAR modulators